1. Field of the Invention
This invention relates to a method and apparatus for non-invasively measuring at least one parameter of a sample, such as the presence and/or concentration of one or more analytes or physical and/or chemical constants characterizing the tissue in a human body part by using photoacoustic spectroscopy.
2. Description of the Related Art
Analysis of samples and measurement of the concentration of components contained therein is a common and important process in chemistry and biology. In particular, the analysis of the biological fluids such as blood, interstitial fluid, urine or saliva to determine the concentrations of various components and to determine the diseases state is important both in diagnosis and in treatment of a variety of diseases including diabetes and cardiac diseases. The measurement of physical and/or chemical constants characterizing the tissue is also effective in diagnosis of various diseases, such as tumors. A representative apparatus for measuring the concentration of an analyte in the blood is the blood glucose meter used by diabetics. Present blood glucose meters for self-testing use a small blood sample taken from the subject by the subject, e.g. by piercing a finger or arm with a needle or lancet, to measure the subject's blood glucose level. An enzyme electrode, for example, is used for measuring the amount of glucose. An enzyme called glucose oxidase (GOD) is fixed on the macromolecule film of the electrode. When blood contacts the film, glucose in the blood reacts with oxygen in the presence of GOD. The glucose concentration can be quantified by measuring the change of oxygen consumed. Currently available blood glucose meters are portable, and are used in management of a diabetic's blood glucose level.
However, the above mentioned method is painful and damages the skin of the subject because it is necessary to prick a part of the body with a needle or a lancet. Therefore, although 5 times or more frequent monitoring in a day is desirable to manage a diabetic's blood glucose level strictly, it is currently restricted to 2 or 3 times per day.
The minimally invasive skin microporation approaches utilizing laser or ultrasound for extracting the blood or the interstitial fluid are disclosed in U.S. Pat. No. 6,074,383 and No. 5,458,140. On the other hand, non-invasive monitoring methods and apparatus using visible light and/or near-infrared light which neither require pricking a part of the body with the a needle or a lancet nor to extract the sample such as blood or interstitial fluid are disclosed in Japanese patents kokai No. 60-236631 and kokai No. 02-191434. The non-invasive measurement, which can determine an analyte or a disease state in a human subject without performing any invasive procedures such as removing a sample of blood or a biopsy specimen, has several advantages. The advantages include ease of use, reduced pain and discomfort, and decreased exposure to potential biohazards.
Visible light here means electromagnetic waves in the range of about 380 nm to about 770 nm; near-infrared light means electromagnetic waves in the range of about 770 nm to about 1500 nm; middle-infrared light means electromagnetic waves in the range of about 1500 nm to about 3000 nm; far-infrared light means electromagnetic waves in the range of about 3000 nm to about 25000 nm.
The above mentioned Japanese patent applications disclose the methods for glucose concentration measurement of the subject such that the near-infrared light of plural wavelengths is irradiated on the skin surface of the subject, and the light which is diffused and/or scattered in the subject is detected, and the detected signals are divided into a reference signal and objective signal, and the glucose concentration is calculated from these signals. It is also disclosed that a tungsten halogen lamp, semiconductor laser (LD), or light emitting diode (LED) can be used as the light source for near-infrared light, and a photodiode (PD) can be used as the detector of the diffused and or scattered infrared light.
Non-invasive spectroscopic monitoring of biological substances using the visible and/or near-infrared light has advantages over using middle-infrared or the far-infrared light. These are high tissue penetration and high analyses capability for the aqueous solution because it has low absorption by water—the main constituent of the human body.
On the other hand, the non-invasive spectroscopic monitoring using the visible and/or near-infrared lights also has disadvantages. The signal which is attributable to molecular vibration is as low as about one-hundredth ( 1/100), and is hard to specify an attribution of the signal as compared with that using the middle- or far-infrared light.
Other methods of non-invasive glucose measurement are also disclosed in U.S. Pat. No. 5,348,002, Japanese patent kokai No. 10-189, and Japanese patent kokai No. 11-235331. These patents disclose methods and glucose concentration measurement apparatuses using near-infrared light irradiated onto the skin of the subject, and a photoacoustic signal generated with result that glucose molecules in the subject absorb energy of the irradiation is detected by a detection means. In photoacoustic spectroscopy disclosed in the patents, a microphone device or a piezoelectric vibrator such as lead zirconate titanate (PZT) ceramics is generally used as the detection means.
However, it is a difficult to get photoacoustic signals with good signal to noise ratio that are adequate for measuring glucose concentration, even after using repetitive measurements and signal averaging, because the generated photoacoustic signals are so weak.
The above-mentioned methods and apparatus for non-invasive monitoring are applicable to other substances and analytes besides glucose, for example, cholesterol, natural fats, and hemoglobin.